SIGNALS FOR RENAL ENDOTHELIAL CAPILLARY MORPHOGENESIS

毛细血管内皮细胞的增殖分化是一种 支持发展的基本过程，专门的器官功能， 并且会痊愈。细胞分化功能紊乱与细胞增殖 毛细血管内皮细胞是病理过程中不可或缺的一部分 肿瘤、纤维化/硬化性疾病、糖尿病神经病变和 肾病。内皮细胞处理来自介质的细胞外信号 通过细胞内信号的整合功能促进血管生成 尚未定义的系统。这项建议解决了这一假设 特异性内皮型酪氨酸激酶信号转导事件 毛细血管样管形成(CTF)。细胞型限制性酪氨酸激酶 在许多发育系统中通过影响调节细胞命运决定 增殖分化。用培养的人肾 微血管内皮细胞，我们已经证明：1)酪氨酸激酶 抑制剂阻断内皮细胞毛细血管形态发生，2)独特的酪氨酸 在支持CTF的限制条件下检测到磷蛋白， 和3)一种新的可能的内皮酪氨酸激酶ETK在以下条件下被诱导 支持CTF的受限条件。我们建议：1)获得完整的 ETK基因的长度，产生ETK抗体，2)识别模式 ETK在胚胎发育、血管生成中的表达，以及3)到 确定这个假定的酪氨酸激酶是否介导了 反映CTF的标记基因产物。这些研究将提供分子 内皮细胞毛细血管形态发生基本过程的定义 并建立工具来探索这一过程的病理变化 糖尿病和癌症。

Proliferation and differentiation of capillary endothelial cells is a fundamental process underpinning development, specialized organ function, and would healing. Disordered differentiated function and proliferation of capillary endothelia are integral to pathological processes ranging from neoplasms, to fibrosing/sclerosing diseases, to diabetic neuropathy and nephropathy. Endothelial cells process extracellular cues from mediators of angiogenesis through the integrated function of intracellular signaling systems which are yet undefined. This proposal addresses the hypothesis that specific endothelial tyrosine kinases signal events mediating capillary-like tube formation (CTF). Cell-type restricted tyrosine kinases regulate cell fate determination in many developmental systems by affecting proliferation and differentiation. Using cultured human renal microvascular endothelial cells, we have shown: 1) tyrosine kinase inhibitors block endothelial capillary morphogenesis, 2) distinct tyrosine phosphoproteins are detected under restricted conditions supporting CTF, and 3) a novel putative endothelial tyrosine kinase, ETK, is induced under restricted conditions which support CTF. We propose; 1) to obtain a full length cDNA for ETK, generate ETK antibodies, 2) to identify patterns of ETK expression during embryonic development, angiogenesis, and 3) to determine whether this putative tyrosine kinase mediates expression of marker gene products reflecting CTF. These studies will provide molecular definition of the essential process of endothelial capillary morphogenesis and establish tools to explore pathological alterations of this process in diabetes and cancer.